The principal type of neuron found in the subthalamic nucleus has rather long sparsely spiny dendrites.[2][3] The dendritic arborizations are ellipsoid, replicating in smaller dimension the shape of the nucleus.[4] The dimensions of these arborizations (1200,600 and 300 μm) are similar across many species—including rat, cat, monkey and human—which is unusual. However, the number of neurons increases with brain size as well as the external dimensions of the nucleus. The principal neurons are glutamatergic, which give them a particular functional position in the basal ganglia system. In humans there are also a small number (about 7.5%) of GABAergicinterneurons that participate in the local circuitry; however, the dendritic arborizations of subthalamic neurons shy away from the border and majorly interact with one another.[5]

The axons of subthalamic nucleus neurons leave the nucleus dorsally. The efferent axons are glutamatergic (excitatory). Except for the connection to the striatum (17.3% in macaques), most of the subthalamic principal neurons are multitargets and directed to the other elements of the core of the basal ganglia.[8] Some send axons to the substantia nigra medially and to the medial and lateral nuclei of the pallidum laterally (3-target, 21.3%). Some are 2-target with the lateral pallidum and the substantia nigra (2.7%) or the lateral pallidum and the medial (48%). Less are single target for the lateral pallidum. In the pallidum, subthalamic terminals end in bands parallel to the pallidal border.[8][9] When all axons reaching this target are added, the main afference of the subthalamic nucleus is, in 82.7% of the cases, clearly the medial pallidum (internal segment of the globus pallidus).

Some researchers have reported internal axon collaterals.[10] However, there is little functional evidence for this.

Anatomical overview of the main circuits of the basal ganglia. Subthalamic nucleus is shown in red. Picture shows 2 coronal slices that have been superimposed to include the involved basal ganglia structures. + and - signs at the point of the arrows indicate respectively whether the pathway is excitatory or inhibitory in effect. Green arrows refer to excitatory glutamatergic pathways, red arrows refer to inhibitory GABAergic pathways and turquoise arrows refer to dopaminergic pathways that are excitatory on the direct pathway and inhibitory on the indirect pathway.

The first intracellular electrical recordings of subthalamic neurons were performed using sharp electrodes in a rat slice preparation.[citation needed] In these recordings three key observations were made, all three of which have dominated subsequent reports of subthalamic firing properties. The first observation was that, in the absence of current injection or synaptic stimulation, the majority of cells were spontaneously firing. The second observation is that these cells are capable of transiently firing at very high frequencies. The third observation concerns non-linear behaviors when cells are transiently depolarized after being hyperpolarized below –65mV. They are then able to engage voltage-gated calcium and sodium currents to fire bursts of action potentials.

Several recent studies have focused on the autonomous pacemaking ability of subthalamic neurons. These cells are often referred to as "fast-spiking pacemakers",[11] since they can generate spontaneous action potentials at rates of 80 to 90 Hz in primates.

Oscillatory and synchronous activity[12][13] is likely to be a typical pattern of discharge in subthalamic neurons recorded from patients and animal models characterized by the loss of dopaminergic cells in the substantia nigra pars compacta, which is the principal pathology that underlies Parkinson's disease.

Strong reciprocal connections link the subthalamic nucleus and the external segment of the globus pallidus. Both are fast-spiking pacemakers. Together, they are thought to constitute the "central pacemaker of the basal ganglia"[14] with synchronous bursts.

The connection of the lateral pallidum with the subthalamic nucleus is also the one in the basal ganglia system where the reduction between emitter/receiving elements is likely the strongest. In terms of volume, in humans, the lateral pallidum measures 808 mm³, the subthalamic nucleus only 158 mm³.[15] This translated in numbers of neurons represents a strong compression with loss of map precision.

Some axons from the lateral pallidum go to the striatum.[16] The activity of the medial pallidum is influenced by afferences from the lateral pallidum and from the subthalamic nucleus.[17] The same for the substantia nigra pars reticulata.[9] The subthalamic nucleus sends axons to another regulator: the pedunculo-pontine complex (id).

The lateropallido-subthalamic system is thought to play a key role in the generation of the patterns of activity seen in Parkinson's disease.[18]

Chronic stimulation of the STN, called deep brain stimulation (DBS), is used to treat patients with Parkinson disease. The first to be stimulated are the terminal arborisations of afferent axons, which modify the activity of subthalamic neurons. However, it has been shown in thalamic slices from mice,[19] that the stimulus also causes nearby astrocytes to release Adenosine Triphosphate (ATP), a precursor to adenosine (through a catabolic process). In turn, adenosine A1 receptor activation depresses excitatory transmission in the thalamus, thus mimicking ablation of the subthalamic nucleus.

Unilateral destruction or disruption of the subthalamic nucleus – which can commonly occur via a small vessel stroke in patients with diabetes, hypertension, or a history of smoking – produces hemiballismus.

As one of the STN's suspected functions is in impulse control, dysfunction in this region has been implicated in Obsessive–compulsive disorder.[20] Artificially stimulating the STN has shown some promise in correcting severe impulsive behavior and may later be used as an alternative treatment for the disorder.[21]

The function of the STN is unknown, but current theories place it as a component of the basal ganglia control system that may perform action selection. STN dysfunction has also been shown to increase impulsivity in individuals presented with two equally rewarding stimuli.[22]

Research has suggested that the subthalamus is an extrapyramidal center. It holds muscular responses in check, and damage may result in hemiballisumus (a violent flinging of the arm and leg on one side of the body).[23]